Diuretics

Question 1

Main site of action for diuretics

Answer 1

lumenal (urine) surface of renal tubule cells

Question 2

Mechanisms of diuretics

Answer 2

·Interactions with membrane transport proteins (thiazides, furosemide, triamterene) • Specific interactions with enzymes (acetazolamide) or hormone receptors (spironolactone) • Osmotic effects preventing water reabsorption (mannitol)

Question 3

How do diuretics affect Na?

Answer 3

Do NOT act at Na/K pump. Diuretics decrease Na reabsorption

Question 4

Which diuretics act at the proximal convoluted tubule?

Answer 4

Carbonic anhydrase inhibitors,

Question 5

Which diuretics act at loop of Henle

Answer 5

High Ceiling Diuretics

Question 6

Which diuretics act on distal convuluted tubule?

Answer 6

Thiazide diuretics

Question 7

Which diuretics act on the collecting tubules?

Answer 7

Potassium sparing diuretics: Aldosterone antagonists and Na-channel blockers

Question 8

Proximal convoluted tubule reabsorption

Answer 8

Almost all metabolites and 60-70% Na is reabsorbed here.

Question 9

What does Carbonic anhydrase do and where is it located? -not on test

Answer 9

CA is on luminal surface of proximal convoluted tubule. Allows for reabsorption of HCO3- and exchanges H for Na (Na is reabsorbed and H is excreted into urine)

Question 10

Carbonic anhydrase inhibitors- example and MOA -not on test

Answer 10

Acetazolamide. Inhibits CA enzyme

Question 11

Carbonic anhydrase inhibitors-clinical uses and toxicities - not on test

Answer 11

Not used in HF. Used for glaucoma and acute mountain sickness (slow progression of pulmonary or cerebral edema). Toxicity: increased urinary pH, K+ wasting

Question 12

Function of Loop of Henle

Answer 12

Water removal from lumen ccurs in descending limb. Active NaCl reabsorption occurs in ascending limb via Na-K-2CL cotransporter.

Question 13

Loop of Henle agents (High ceiling diuretics)- examples

Answer 13

Furosemide, torsemide and bumetanide

Question 14

High ceiling diuretics MOA

Answer 14

Inhibit NaCl transport (Na+-K+-2Cl–transporter) in thick ascending limb of loop of Henle. This results in increased Mg and Ca excretion into lumen to offset the lumen positive potential

Question 15

High ceiling diuretics pharmacokinetics

Answer 15

Rapid oral absorption. Renal secretion and filtration

Question 16

High ceiling diuretics clinical use in CHF

Answer 16

Preferred diuretic class b/c efficiency. Used in HF patients with volume overload to eliminate pulmonary congestion and peripheral edema. Enhanced with salt restrictions. Furosemide most commonly used.

Question 17

Why do HF patients have reduced diuretic response?

Answer 17

decreased drug delivery to kidney due to decreased Renal Blood Flow and hypoperfusion activation of RAAS and SNS

Question 18

Additional uses of high ceiling diuretics besides HF

Answer 18

Acute pulmonary edema, refractory edema, Hypercalcemia

Question 19

Explain drug combos commonly used in refractory edema

Answer 19

High ceiling diuretic can be combined with Thiazide (blocks distal tubule Na reabsorption which is sometimes increased with high ceiling due to increased Na delivery to this segment), or Aldosterone antagonists to improve survival and ameliorate K wasting.

Question 20

High ceiling diuretics adverse reactions

Answer 20

Hypokalemic metabolic alkalosis via enhanced secretion of K+ and H(can cause ectopic pacemakers), ototoxicity,Hyperuricemia/hyperglycemia, hypomagnesemia

Question 21

Loop diuretic effect on plasma electrolytes- efficacy, K, H, Ca, Mg, Urate

Answer 21

high efficacy, decreased K, decreased H, decreased Ca, decreased Mg, increased urate

Question 22

Function of distal convoluted tubule

Answer 22

Na/Cl co transporter facilitates reabsorption of NaCl. Also site of active Ca reabsorption via Na/Ca exchanger which is regulated by parathyroid hormone

Question 23

Thiazide examples

Answer 23

Hydrochlorothiazide - Chlorthalidone - Metolazone

Question 24

Thiazide MOA

Answer 24

inhibiting the Na+/Cl- cotransporter and increasing urinary excretion of NaCl (modest diuretic effect, only 5-10% of filtered Na+ is reabsorbed here). Increases reabsorption of Ca

Question 25

Thiazide pharmacokinetics

Answer 25

All abosorbed orally. • Hydrochlorothiazide: Prototype thiazide, twice daily dose • Chlorthalidone - Metolazone: longer durations → once daily dosing. May precipitate gout attack due to secretion by organic acid secretory system

Question 26

Thiazide clinical uses

Answer 26

CHF: Synergistic effect with loop diuretics. Hypertension (first line) and Hypercalcuria (decreases incidence of kidney stones)

Question 27

Thiazide adverse rxns

Answer 27

Hypokalemia (ectopic pacemakers), Hyperglycemia, hyperuricemia, hyperlipidemia

Question 28

Effect of thiazide on plasma electrolytes: efficacy, K, H, Ca, Mg, Urate

Answer 28

mid-high efficacy, slightly decreases K, slightly decreases H, increases Ca, increases urate, no change to Mg

Question 29

What part of the kidney does aldosterone target? What does aldosterone do?

Answer 29

Collecting tubules- aldosterone increases number and activity of Na and K channels, and Na/K pump

Question 30

function of collecting tubules

Answer 30

Only 2-5% of NaCl reabsorption occurs at this site. Na and K transport occur in principal cells via channels and Na/K pump (K excretion is coupled to Na reabsorption).

Question 31

Aldosterone Antagonists examples

Answer 31

Spironolactone / Eplerenone

Question 32

Na+-channel Blockers xamples

Answer 32

Triamterene / Amiloride

Question 33

Aldosterone antagonists MOA

Answer 33

Competitive antagonist at aldosterone receptor, binds to cytosolic receptor preventing enhancement of protein synthesis. Prevents Na reabsorption which makes lumen more positive, thus less K and H move into urine. Only mild diuresis

Question 34

Na channel blocker MOA

Answer 34

Direct effect to block the Na+-channels on collecting duct lumen to decrease Na+ reabsorption (and thus decreases coupled K+ secretion)

Question 35

Pharmacokinetics of spironolactone, eplerenone, triamterene/amiloride

Answer 35

Spironolactone: 1-2 doses/day; poor oral absorption. Slow onset of action. • Eplerenone : 1-2 times/day orally, metabolized by CYP3A4.
• Triamterene / Amiloride: Triamterene metabolized in liver, amiloride excreted unchanged thus given less frequently. Effect within 2-4 hrs, but 1-3 days to maximal effect.

Question 36

Clinical uses of K sparing diuretics

Answer 36

CHF, Hyperaldosteronism (spironolactone and eplerenone), Hirsutism of polycystic ovary syndrome via block of androgen receptor (spironolactone), hypertension (in combo with thiazide)

Question 37

Clinical use of K sparing diuretics in CHF

Answer 37

Aldosterone antagonists improve survival by blocking aldosterone receptors on heart rather than kidney. Anti-remodeling action prevents hypertrophy induced by aldosterone. Raises serum K to counter K wasting diuretics

Question 38

Adverse rxns of K sparing diuretics

Answer 38

Hyperkalemia, endocrine abnormalities (spiro)